Despite intense research efforts, drug addiction persists as a serious public health problem for which no effective treatment exists. Although they are likely beneficial, traditional herbal preparations are not widely considered to be viable options for the management of drug addiction, due in part to the paucity of clinical and preclinical studies examining their efficacy and safety. Recent studies by our research team and others have demonstrated that the tetrahydroprotoberberine (THPB) alkaloid, levo-tetrahydropalmatine (l-THP), isolated from crushed roots of the herb Stephania delavayi Diels (di bu long) may be useful for treating drug addiction. THPBs are naturally occurring alkaloids found in plants from the botanical genera Corydalis and Stephania and are contained in many traditional Chinese herbal preparations. Two of these species, Corydalis ambigua (yan hu suo) and Stephania tetranda (fang ji) are among the 50 fundamental herbs in Chinese herbology and have been used for their sedative, neuroleptic and analgesic properties. Several THPBs, most notably l-THP and the levo isomer of stepholidine (l-SPD) have pharmacological profiles that make them ideally suited for treating drug addiction, including antagonist and/or partial agonist effects at a variety of dopamine (DA) receptors. Further characterization of the effectiveness of THPBs in preclinical models of drug abuse should facilitate our understanding of which THPB-containing preparations will have the greatest utility for treating drug-dependent populations. This proposal builds on preliminary data demonstrating that l-THP reduces cocaine-seeking behavior in preclinical rat models and that l-THP reduces drug craving and relapse in recovering heroin addicts. The two isolated THPB constituents selected for testing (l-THP and l-SPD) have distinct properties that may make them safer and more effective compared to existing DA receptor antagonist drugs. The proposed studies will use preclinical rat self-administration based procedures to compare the effects of l-THP and l-SPD with those of the non-selective DA receptor antagonist, fluphenazine, and an "atypical" anti- psychotic in paradigms designed to examine the ability of these agents, when administered acutely or chronically, to curb cocaine use and to prevent the relapse of cocaine seeking induced by drug re-exposure, the onset of stress, and exposure to drug-associated conditioned cues. The occurrence of potential undesirable effects as a consequence of chronic administration of these compounds, including sedation, extrapyramidal symptoms, weight gain abuse liability, and hepatotoxicity will also be examined. It is anticipated that, through preclinical investigation of the effectiveness and safety of isolated THPBs, we will be able to advance the use of herbal preparations containing these THPBs as viable treatments for drug addiction. PUBLIC HEALTH RELEVANCE: This project will examine the usefulness of herbal preparations containing the tetrahydroprotoberberine (THPB) alkaloids, levo-tetrahydropalmatine (l-THP) and levo-stepholidine (l-SPD), for the treatment of drug addiction. l-THP and l-SPD isolated from the roots of Stephania delavayi Diels will be tested for their effectiveness in preclinical rat models of cocaine use and relapse and for the occurrence of potential use-limiting side effects. The efficacy and safety of these herbal constituents will be compared to those of a representative dopamine receptor antagonist drug to test the hypothesis that they will show improved anti-addictive properties and reduced undesirable side effects.